477 Immunohistochemically recognised bile salt export protein is unremarkably expressed at the canaliculus in persons with disease

Knisely, A. S.; Meier, Yvonne; Stieger, Bruno; Portmann, B; Rayner, A.C.; Strautnieks, S.S.; Thompson, R.J.; Houwen, Roderick; Klomp, L.W.J.; Bull, LN

doi:10.1016/s0270-9139(03)80519-0

Cited by 4 publications

(4 citation statements)

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“…Bile salt concentrations in bile of PFIC-3 patients are normal, [32][33][34][35][36][37][38][39] which might be explained by preserved canalicular BSEP expression as demonstrated in this study. Elevated bile salt concentrations in the blood of PFIC-3 patients consequently must be attributable to other mechanisms than BSEP downregulation and might include impaired sinusoidal uptake of bile salts or increased efflux back into blood.…”

Section: Discussionsupporting

confidence: 60%

“…34 Although our children with a low-␥GT cholestasis having a PFIC-1 genotype was not ruled out, this seems unlikely, because BSEP expression and its canalicular localization were reported to be unaltered in PFIC-1 disease. 35 Milder forms of BSEP mutations were recently identified to cause a second form of benign recurrent intrahepatic cholestasis (BRIC-2). 36 However, BSEP localization in BRIC-2 patients was not investigated in that study.…”

Section: Discussionmentioning

confidence: 99%

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Expression and localization of hepatobiliary transport proteins in progressive familial intrahepatic cholestasis

et al. 2005

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Mutations of the bile salt export pump (BSEP) or the multidrug resistance P-glycoprotein 3 (MDR3) are linked to impaired bile salt homeostasis and lead to progressive familial intrahepatic cholestasis (PFIC)-2 and -3, respectively. The regulation of bile salt transporters in PFIC is not known. Expression of hepatobiliary transporters in livers of ten patients with a PFIC phenotype was studied by quantitative reverse transcription polymerase chain reaction, Western blotting, and immunofluorescence microscopy. PFIC was diagnosed by clinical and laboratory findings. All patients could be assigned to PFIC-2 or PFIC-3 by the use of BSEP-and MDR3-specific antibodies and by MDR3 gene-sequencing. Whereas in all PFIC-2 patients, BSEP immunoreactivity was absent from the canalicular membrane, in three PFIC-3 livers, canalicular MDR3 immunoreactivity was detectable. Serum bile salts were elevated to 276 ؎ 233 and to 221 ؎ 109 mol/L in PFIC-2 and PFIC-3, respectively. Organic anion transporting polypeptide OATP1B1, OATP1B3, and MRP2 mRNA and protein levels were reduced, whereas sodium taurocholate cotransporting polypeptide (NTCP) was only reduced at the protein level, suggesting a posttranscriptional NTCP regulation. Whereas MRP3 mRNA and protein were not significantly altered, MRP4 messenger RNA and protein were significantly increased in PFIC. In conclusion, PFIC-2 may be reliably diagnosed by immunofluorescence, whereas the diagnosis of PFIC-3 requires gene-sequencing. Several mechanisms may contribute to elevated plasma bile salts in PFIC: reduced bile salt uptake via NTCP, OATP1B1, and OATP1B3, decreased BSEP-dependent secretion into bile, and increased transport back into plasma by MRP4. Upregulation of MRP4, but not of MRP3, might represent an important escape mechanism for bile salt extrusion in PFIC. Supplementary material for this article can be found on the HEPATOLOGY website (http://www.interscience.wiley.com/jpages/0270-9139/ suppmat/index.html). (HEPATOLOGY 2005;41:1160-1172

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Section: Discussionsupporting

confidence: 60%

Section: Discussionmentioning

confidence: 99%

Expression and localization of hepatobiliary transport proteins in progressive familial intrahepatic cholestasis

et al. 2005

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“…50 51 A recent preliminary study revealed unremarkable BSEP expression at the canalicular membrane of hepatocytes in PFIC1 patients, but BSEP function was not addressed. 58 In addition, the expression of P-glycoproteins at the canalicular membrane was not affected in a PFIC1 patient. 50 There are additional hypotheses for the function of FIC1; it might be a bile salt transporter for hydrophilic bile salts or could play a role in ion transport, based on the 30% homology with P-type ATPases that function as Ca 2+ transporters.…”

Section: Transporter Defects Affecting Bile Formationmentioning

confidence: 90%

Genetics of familial intrahepatic cholestasis syndromes

Mil

Houwen²,

Klomp³

2005

Journal of Medical Genetics

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“…(3,5,(8)(9)(10) On the other hand, a genotype with biallelic predicted protein truncating mutations (PPTMs) has been associated with a more severe phenotype (with regard to NLS, response to siEHC and incidence of hepatocellular carcinoma (HCC)). (3,5,11,12) We have unpredictable effect on BSEP protein function. Three patients who were compound heterozygous for BSEP1/1 (carrying one p.D482G mutation on one allele and one p.E297G mutation on the other allele) were excluded from the analysis to allow an analysis of only homozygous BSEP1/1 patients.…”

Section: Introductionmentioning

confidence: 99%

Genotype-phenotype relationships of truncating mutations, p.E297G and p.D482G in bile salt export pump deficiency

Felzen

Wessel²,

Gonzalès³

et al. 2023

JHEP Reports

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477 Immunohistochemically recognised bile salt export protein is unremarkably expressed at the canaliculus in persons with disease

Cited by 4 publications

References 0 publications

Expression and localization of hepatobiliary transport proteins in progressive familial intrahepatic cholestasis

Expression and localization of hepatobiliary transport proteins in progressive familial intrahepatic cholestasis

Genetics of familial intrahepatic cholestasis syndromes

Genotype-phenotype relationships of truncating mutations, p.E297G and p.D482G in bile salt export pump deficiency

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